JP2834581B2 - Pharmaceutical composition comprising 3,4-diarylchroman for inhibiting bone loss - Google Patents

Abstract

Methods and pharmaceutical compositions for reducing bone loss are disclosed. 3,4-diarylchromans and their pharmaceutically acceptable salts are formulated into medicaments for the treatment of bone loss due to osteoporosis or other conditions. An exemplary 3,4-diarylchroman is centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)phenyl)-7-methoxy-chroman). Formulations include tablets and other forms suitable for oral administration and controlled-release subdermal implants.

Description

BACKGROUND OF THE INVENTION Bone remodeling is a dynamic process in which skeletal weight and structure are updated and maintained. This update (re
newal) and maintenance are the balance between bone resorption and bone formation, with osteoclasts and osteoblasts
st) is considered to be the two main participants in this update process. Osteoclasts initiate their remodeling cycle by synthesizing new bone matrix within pits and resorbing subsequently voided bone in the osteoblasts as they deposit . Osteoclast and osteoblast activity is regulated by a complex interaction between systemic hormones and local production of growth factors and cytokines at the site of active remodeling.

Imbalances in bone remodeling have been linked to conditions such as osteoporosis, Paget's disease, and hyperparathyroidism. Osteoporosis, characterized by a decrease in skeletal weight, is one of the most common diseases in postmenopausal women, and often debiliating the spine, hip and wrist.
And painful fractures.

Approximately 25% of postmenopausal women suffer from osteoporosis, and it is generally accepted that the etiology of this disease involves a decrease in circulating estrogens (Komm et al., Science 241 : 8).
1-84, 1988). Komm et al. Further noted that 15% of U.S. Caucasian women at risk for hip
Or reports 247,000 hip fractures annually in women over the age of 45.

The cost of osteoporosis is enormous, both personally and financially. In 1984, 145,000 inpatient fracture reductions and 107,000 hip arthroplasties and replacements were performed on women over the age of 65. Among patients living alone prior to a hip fracture, 15% to 20% require long-term care as a result of the fracture and cannot regain independence for one year after the fracture Was. In 1986, the total financial cost of treating osteoporosis, including fractures, in the United States was $ 70-100 billion (Peck et al., Am.
J. Med. 84: 275-282,1988).

Bone loss associated with osteoporosis has been halted by administration of exogenous estrogens. To be valid,
Estrogen therapy must be started within a few years of the onset of menopause and must last 10 to 15 years according to Thorneycroft ( Am. J. Obstet. Gynecol. 160 : 13
06-1310, 1989). Although there are several different types of estrogens, 17-β-estradiol is the major estrogen found naturally in premenopausal women, and is often the compound of choice for therapeutic use. However, at the recommended dosage, there are considerable side effects, the most troublesome being the well-established correlation of endometrial and breast cancer with estrogen therapy. The incidence of carcinoma is dose-dependent and time-dependent.

Avoidance of this cancer risk has been achieved by the concomitant use of progesterone with estrogens. However,
This combination causes an unacceptable menstrual recovery for many women. A further disadvantage is that the long-term effects of this progesterone have not been well measured. Thus, the majority of women need an alternative to hormone replacement therapy that can safely prevent the rapid bone loss associated with their menopause.

Centchroman is a non-steroidal compound known to have anti-estrogenic activity. In India, it is used as an oral contraceptive (eg, Salman et al., US Pat. No. 4,447,622; Si
ngh et al., Acta Endocrinal (Copenh) 126 : 444-450,199
2; Grubb, Curr.Opin.Obstet.Gynecol. 3 : 491-495, 19
91; Sankaran et al., Contraception 9 : 279-289, 1974;
See Indian Patent No. 129187. ) Has also been investigated as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 : 781-78).
3,1989), and has not previously been shown to have any effect on bone resorption.

There is a need in the art for compositions and methods useful in bone loss, particularly bone loss associated with osteoporosis. Further, there is a need for such compositions that lack the undesirable side effects of estrogen. The present invention provides such compositions and methods, and also
It also offers other related advantages.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the effect of St. chroman on bone loss in ovariectomized mice.

FIG. 2 shows the effect of St. chroman on cancellous bone volume in the proximal tibia of ovariectomized rats.

FIG. 3 shows the effect of centchroman on bone resorption (left) and uterine weight (right) in ovariectomized rats.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinoethoxy) phenyl). -7-Methoxy-chroman) is an effective inhibitor of bone loss in ovariectomized mice and rats. These animal models are close to the post-menopausal state and are generally recognized as models for osteoporosis. Thus, these data indicate that the 3,4-diarylchromans are useful as therapeutic agents for reducing bone loss in mammals, including primates, such as humans.

In the present invention, the following formula (I): Or a pharmaceutically acceptable salt thereof is used to reduce bone loss in a patient.

In formula (I), R1, R4 and R5 are independently hydrogen, halo, trifluoromethyl, lower alkyl, lower alkoxy or tertiary amino lower alkoxy; and R2 and
R3 is independently H or lower alkyl. As used herein, the term "lower alkyl" refers to straight and branched chain alkyl groups containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl. , N-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like. The term "lower alkoxy" refers to straight and branched chain alkoxy groups containing 1 to 6 carbon atoms, such as methoxy,
Ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethyl-butoxy, 2,3-dimethylbutoxy, and the like. “Halo”
Includes chloro, fluoro, bromo and iodo. The tertiary amino group can be a dialkylamine such as dimethyl, diethyl, dipropyl, dibutyl or polymethyleneimine such as piperidine, pyrrolidine, N-methyl piperazine or morpholine. Preferred compounds include those wherein R1 is lower alkoxy; R2 and R3 are lower alkyl, especially methyl; R4 is H; and R5 is tertiary amino lower alkoxy of the polymethyleneimine type. In a particularly preferred embodiment, R1
Is in its 7-position and is lower alkoxy, especially methoxy; each of R2 and R3 is methyl and R4 is H
And R5 is in the 4-position and is a tertiary amino lower alkoxy group such as pyrrolidinoethoxy.

It is preferred to use compounds of structure (I) in their trans configuration. These compounds can be used as a racemic mixture or the isolated d-
Alternatively, the 1-enantiomer can be used.

Particularly preferred compounds for use in the present invention are St. chroman (II): It is.

Although showing only one enantiomer, structure (II) above is used herein to refer to the trans configuration of the 3- and 4-phenyl groups, and its d
It will be understood to include both-and 1-enantiomers, as well as racemic mixtures thereof.

3,4-Diarylchromans can be prepared by known methods, for example, C
arney et al. U.S. Pat.No. 3,340,276 to Bolger, U.S. Pat.No. 3,822,287 to Bolger, and Ray et al., J. Med.
19 : 276-279, 1976, which are incorporated herein by reference. The conversion of its cis isomer to its trans configuration by organometallic base-catalyzed isomerization is described in US Pat. No. 3,822,28.
No. 7 discloses it. The optically active d- and 1-enantiomers are incorporated by reference in U.S. Patent No. 4,447,622, which forms an optically active acid salt that is subjected to alkaline hydrolysis to create the desired enantiomer. ) Can be prepared as disclosed by Salman et al.

In the present invention, 3,4-diarylchromans can be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic and mineral acids. Examples of such salts are organic acids, for example, salts of formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, and the like. including. Suitable inorganic acid-addition salts include salts such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids.
These acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. it can.

3,4-Diarylchromans and their salts are useful in human and veterinary medicine for regulating bone metabolism. These compounds include, for example, osteoporosis (including postmenopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, malignant hypercalcemia, and excessive rates of bone regeneration. It can be useful in treating patients suffering from bone loss due to other conditions characterized by bone formation at a rate of resorption and / or reduction.

For use in the present invention, 3,4-diarylchromans and pharmaceutically acceptable salts thereof are used in accordance with conventional methods to prepare pharmaceuticals for parenteral, oral, nasal, rectal, subcutaneous or transdermal administration. To provide a pharmaceutically acceptable carrier. The formulation may further comprise one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients,
And can be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release subcutaneous implants, tablets, and the like.
Those of skill in the art will understand, in an appropriate manner, and acceptable practice, for example, Remington's Pharmaceutical Sciences, Gennaro,
These compounds can be formulated according to those disclosed in ed., Mack Publishing Co., Easton, PA, 1990, which is incorporated herein by reference in its entirety.

Oral administration is preferred. Thus, the active compounds are prepared in forms suitable for oral administration, for example, as tablets or capsules. Typically, a pharmaceutically acceptable salt of the compound is combined with a carrier and formed into tablets. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate, and the like. Such compositions may further comprise one or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers,
Contains colorants, etc.

The pharmaceutical composition is administered at daily to weekly intervals. An “effective amount” of such a pharmaceutical composition is an amount that provides a clinically significant inhibition of bone loss. Such amounts will depend, in part, on the particular condition, age, weight, and general health of the patient to be treated, as well as other factors which will be apparent to those skilled in the art. Generally, inhibition of bone loss is manifested as a statistically significant difference in lattice bone volume between the treated and control groups. This can be seen, for example, as a 5-10% or more difference in vertebra bone weight or bone mineral content over a two year period. Data from acceptable animal models, such as ovariectomized mice or rat models of osteoporosis, generally predict doses in humans, within an order of magnitude. For example,
Therapeutic dosage for the treatment of osteoporosis is generally between 0.01 and 50 mg / kg / day, preferably between 0.05 and 10 mg / kg / day.
Days, most preferably in the range of 0.1 to 5.0 mg / kg / day. The use of a cis-isomer or a ceramic mixture may require a dose at the upper end of the range described above.

The pharmaceutical compositions can be administered in unit dosage form on a daily to weekly basis. Alternatively, they can be provided as a controlled release formulation suitable for subcutaneous implantation. Implants are formulated to provide for release of the active compound over a desired period of time, which can be up to several years. Controlled release formulations are described, for example, in Sanders et al., J. Pharm. Sci. 73 : 1294-2297,19 .
84; U.S. Patent No. 4,489,056; and U.S. Patent No. 4,210,644
Nos. 4,028,098, 5,81,098, 5,098,098, and 5,985,898, which are incorporated herein by reference.

The following examples are provided for illustration, not limitation.

Example 1 The ability of St. chroman to prevent estrogen deficiency-induced osteoopenia was evaluated in an ovariectomized mouse model. 24 Female Swiss-Web
Ster mice (8 years old) underwent ovariectomy or sham surgery prior to the start of the 4-week treatment protocol. For an ovariectomy, a flank incision through the skin, muscles and peritoneum is made on each side, and the ovaries are positioned free of adhesive fat and connective tissue and dissected, and Removed. In the sham procedure, the ovaries were removed from the body and replaced. In all animals, the peritoneum and muscles were sutured together and the skin incision was closed with a trauma clip.

St. chroman was dissolved in a minimal amount of dimethyl sulfoxide and diluted in an oil medium to a concentration of 50 μg / 100 μl. The mice were injected subcutaneously with St. chroman or oil vehicle for 1 week for 4 weeks according to the following outline.
Treated twice a week; sham / oil medium; OVX / oil medium; OV
X / 50 μg Saint chroman twice a week. 8 in each group
There were animals.

At the end of the 4-week St. chroman treatment, mice were anesthetized with ether and killed by cervical amputation. Immediately after killing, the femurs are removed and fixed in 70% ethyl alcohol (EtoH), and a series of increasing alcohol concentrations: 95% EtoH for 24 hours followed by 10% for each 24 hours
Dehydrated in three changes of 0% EtoH. Last 100% Et
After oH, the femurs were cleaned in two changes of xylene and then undecalcified and treated as previously described (Bain et al., Stain Te
(Chnology 65 : 159-163, 1990). An anterior section 5 μm thick of the distal metaphyses of the femur was placed in a Reichert-Jung equipped with a tungsten-carbide knife.
Cut on a 2050 rotation microtome. This 5 μm section was placed on a glass slide and Goldner's
Stained with s3 color stain.

Histomorphometric measurements of the distal metaphysis were obtained from Olympus BH-
2. Camera lucida equipped with visible light / external fluorescence microscope (Scient
Bioquant Bone Morphometry Program (B) interfaced through ific Instruments, Inc., Redmond, WA
iometrics, Inc., Nashville, TN). The morphometric measurement of lattice bone volume (BV / TV) was performed in a tissue space greater than 0.25 mm from its growth plate-metaphyseal junction to exclude the primary spongy material (Spongiosa).

The data shown in FIG. 1 is expressed as mean ± SD for each group. Comparison of the lattice volume of the distal femur
atriew® statistical program (Abacus Concepts,
Inc., Berkeley, (A). The difference in processing indicated by this ANOVA is
Comparisons were made using unnett's multiple comparison procedure. P less than 0.05
Values are considered significant.

In ovariectomized mice treated with an oil medium,
A 50% reduction in the lattice capacity of the distal femur compared to sham animals treated with vehicle was observed. In ovariectomized animals treated with 50 μg of St. chroman twice a week, this bone loss was completely prevented.

Example 2 To evaluate the effect of centchroman on bone resorption and bone weight, 54 female Sprague-Dawley rat skeletons were treated with tritiated tetracycline ( ³ H-T; Dupont NEMR®).
esearch Products, Boston, Mass.) for 4 consecutive weeks. Animals received 12-15 injections of 15 μCi each for a total of about 200 μCi per animal. After 3 days of the last ³ H-T injection, killed 8 animals as a baseline control and the remaining animals,
Estrogen (E2) or St. chroman (C) treatment was performed randomly as follows: sham / placebo; ovariectomy (OVX) / placebo; ovariectomy / E2 (0.05 mg / kg /
Day); Ovariectomy / C (0.05mg / kg / day); Ovariectomy / C (0.5m
g / kg / day); and ovariectomy / C (5.0 mg / kg / day). The hormonal treatment can be performed using a matrix of cholesterol, lactose, cellulose, phosphate and stearate (Innovative) calculated to deliver the dosages indicated above.
(Research, Toledo, OH). In addition to quantifying bone resorption using the ³ HT test described above, femoral and spinal bone weights are also measured to record changes in bone physical properties, and quantitative histomorphometry is performed. It was used to compare changes in the lattice bone volume of the tibia.

Sixty days after the start of the treatment protocol, animals were anesthetized with ether and killed by neck transection. Immediately after killing, the uterus was removed and the weight recorded; both femurs and three thoracic vertebrae (T11-T13) were excised for bone resorption assays: one tibia and the first lumbar vertebrae (lumbar v).
ertebra) collected for measurement of the physical properties of bone;
The second tibia was then excised and processed for bone histomorphometry. All tissues were first fixed in 70% ethyl alcohol (EtoH) and dehydrated in an ascending series of up to 100% EtoH. After the last exchange of 100% EtoH, the samples were processed according to the assay protocol outlined below.

Assays for whole bone resorption are provided by Klein and Jackman ( Calicifie
d Tissue Research 20; 275-290,1976) by essentially disclosed as before - based on the level of ³ H-T retained in the labeled femur and in the spine. Briefly, samples were defatted in three changes of chloroform each 24 hours and dried at 100 ° C. for 24 hours and their weight recorded. To extract ³ HT,
The femurs and vertebrae were demineralized in 15 ml of 0.5N hydrochloric acid (Hcl) and their supernatants were decanted and stored. 625 μl to determine tritium levels
Aliquots are added to 10 ml of Optiflor scintillation fluid (Pa
pipette into glass scintillation vials containing ckard Instruments, Meriden, CT)
The ³ H-T levels were counted on a liquid scintillation spectrometer (Beckman LS 1800).

After EtoH dehydration, samples for bone weighing were defatted in three changes of chloroform each 24 hours and dried in an oven overnight. Bone weight was expressed as mg dry weight per gram body weight.

After the last 100% EtoH treatment, the tibia was cleaned and decalcified in two changes of xylene,
And essentially as disclosed by Bain et al. ( S
tain Technology 65 : 159-163,1990)
Embedded in plastic. A 5 μm thick anterior section of the proximal tibia was placed on a Reichert-Jung 2050 rotating microtome equipped with a tungsten-carbide knife.
ica Instruments, Nusslock, Germany).
This 5 μm section was stained with Goldner's three-color stain.

Histomorphometric measurements of the proximal tibia were made using Olympus BH-2.
Lucida (Scientif camera with visible / infrared microscope)
Bioquant Bone Morphometry Program interfaced via ic Instruments, Inc., Redmond, WA)
(Biometrics, Inc., Nashville, TN). The morphometric measurement of lattice bone volume (cn.BV/TV)
It was performed in a 3.0 mm ² tissue space 1.5 millimeters from the metaphyseal junction - the growth plate to exclude primary spongy material. The minimum of four separate sections was determined from each animal.

Analysis of uterine weight, bone resorption assays, physical properties of bone and histomorphometry of bone distal femur were performed using the Statview® statistical program (Abacus Concepts, Inc., Berkele
y, based on variance analysis (ANOVA) using (A). When significant differences were indicated by this ANOVA, control and treatment means were compared using Dunnett's multiple comparison procedure. P values less than 0.05 are considered significant.

Ovariectomy led to a significant decrease in uterine wet weight compared to sham-vehicle treated animals. Estrogen replacement restored uterine weight to sham values, whereas centchroman treatment had no statistically significant effect on uterine weight, even at the highest dose of 5.0 mg per day. As signs of increased bone resorption, ovariectomy reduced the skeletal retention of ³ H-T in femurs and vertebrae (respectively, Table 1 and 2). As expected,
Estrogen treatment increased the skeletal retention of ³ H-T.
Centchroman, the dosage in skeletal retention of ³ H-T at both skeletal sites - by causing dependent increase mimic the effects of estrogen on bone resorption (gamma
^{The two} values are equal to 0.96 and 0.92 for the thigh and spine, respectively. ).

St. chroman's ability to inhibit bone resorption and prevent bone loss was confirmed by measuring lattice bone volume in the tibia and femur and spine bone weighing. Compared to ovariectomized rats treated with vehicle, centchroman caused a dose-dependent increase in the lattice volume of the proximal tibia (FIG. 2; γ ² = 0.99). Similarly,
Saint chroman had a dose-dependent effect on bone weight in the femur and spine.

Briefly, these data indicate that the ability of St. chroman to prevent bone loss in ovariectomized rats is independent of any apparent uterotrophic activity. This is clearly shown in FIG. 3 by combining uterine weight data with bone resorption data from the femur to show the independent effect of St. chroman on these two tissues.

Although the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is self-evident that certain changes and modifications can be made within the scope of the appended claims. Would.

──────────────────────────────────────────────────の Continued on the front page (72) Inventor Piggot, James Earl. United States, Washington 98021, Bozel, Meridian Avenue West 23612 (72) Inventor, Bain, Steven Dee. United States, Washington 98177, Seattle, Northwest Onehand Dread Eighties 123 (56) Reference Int, J. et al. Cancer, 43 [5] (1989) p. 781-783 Agents and Actions, 18 [5/6] (1986) p. 596-599J. Med. Chem. , 29 [9] (1986) p. 1801-1803 J.C. Med. Chem. , 29 [2] (1976) p. 276-279 Endocrinology, 118 [1] (1986) p125-131 Breast Cancer Reseach and Treatment, 10 (1987) p. 31-35 Calcif. Tissue In e. , 36 (1984) p123-125 Endocrinology, 133 [6] (1993) p. 2787-2791 Arch. Intern. Med. , 151 [9] (1991) p. 1842-1847 Fertil. Seeril. , 65 [6] (1996) p. 1083-1089 J.C. Bone Mineral Res. , 12 (suppl 1) (1997) F 484 (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (43)

(57) [Claims] 1. The following formula for reducing bone loss in a patient suffering from bone loss due to osteoporosis, Paget's disease or hyperparathyroidism: Wherein R1, R4 and R5 are independently hydrogen, hydroxy, halo, trifluoromethyl, lower alkyl, lower alkoxy or tertiary amino lower alkoxy; and R2 and R3 are independently hydrogen or lower alkyl. is there. A pharmaceutical composition comprising an effective amount of a bone loss inhibiting compound represented by さ れ る or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. (2) wherein R1 is lower alkoxy, R2 and
The pharmaceutical composition according to claim 1, wherein R3 is lower alkyl, R4 is hydrogen, and R5 is tertiary amino lower alkoxy. 3. The pharmaceutical composition according to claim 1, wherein R1 is methoxy. 4. The method of claim 1, wherein R2 and R3 are methyl.
A pharmaceutical composition according to claim 1. 5. The pharmaceutical composition according to claim 1, wherein R4 is hydrogen. (6) wherein R5 is The pharmaceutical composition according to claim 1, which is 7. The pharmaceutical composition according to claim 1, wherein the compound is an isolated d- or 1-enantiomer. 8. The pharmaceutical composition according to claim 7, wherein the compound is an isolated 1-enantiomer. 9. The compound according to claim 1, The pharmaceutical composition according to claim 1, which is (10) the compound, The pharmaceutical composition according to claim 1, which is 11. The pharmaceutical composition according to claim 10, wherein the compound is an isolated d- or 1-enantiomer. 12. The pharmaceutical composition according to claim 11, wherein the compound is an isolated 1-enantiomer. 13. The method of claim 1, wherein the patient is a post-menopausal woman.
A pharmaceutical composition according to claim 1. 14. The pharmaceutical composition according to claim 1, wherein the composition is in a form suitable for oral administration. 15. The pharmaceutical composition according to claim 1, wherein the compound is administered at a dose of 0.1 to 5.0 mg / kg patient weight / day. 16. The composition is administered at daily to weekly intervals.
The pharmaceutical composition according to claim 1. 17. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a subcutaneous implant. 18. A method for treating osteoporosis, comprising the following formula: Wherein R1, R4 and R5 are independently hydrogen, hydroxy, halo, trifluoromethyl, lower alkyl, lower alkoxy or tertiary amino lower alkoxy; and R2 and R3 are independently hydrogen or lower alkyl. is there. A pharmaceutical composition comprising an isolated d- or l-enantiomer of a bone loss inhibiting compound represented by｝ or a pharmaceutically acceptable salt thereof in an amount sufficient to inhibit bone resorption . 19. A compound according to claim 19, wherein R1 is lower alkoxy, R2 and R3 are lower alkyl, R4 is hydrogen, and R5
The pharmaceutical composition according to claim 18, wherein is a tertiary amino lower alkoxy. 20. The pharmaceutical composition according to claim 18, wherein R1 is methoxy. 21. The method of claim 21, wherein R2 and R3 are methyl.
19. The pharmaceutical composition according to 18. 22. The pharmaceutical composition according to claim 18, wherein R4 is hydrogen. (23) wherein R5 is 19. The pharmaceutical composition according to claim 18, which is (24) the compound, 19. The pharmaceutical composition according to claim 18, which is (25) the compound, 19. The pharmaceutical composition according to claim 18, which is 26. The patient of claim 18, wherein the patient is a post-menopausal woman.
A pharmaceutical composition according to claim 1. 27. The following formula for reducing or preventing bone loss in a patient: Wherein R1, R4 and R5 are independently hydrogen, hydroxy, halo, trifluoromethyl, lower alkyl, lower alkoxy or tertiary amino lower alkoxy; and R2 and R3 are independently hydrogen or lower alkyl. is there. A pharmaceutical composition comprising an effective amount of a bone loss inhibiting compound represented by さ れ る or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 28. wherein R 1 is lower alkoxy, R 2 and R 3 are lower alkyl, R 4 is hydrogen, and R 5
28. The pharmaceutical composition according to claim 27, wherein is a tertiary amino lower alkoxy. 29. The pharmaceutical composition according to claim 27, wherein R1 is methoxy. 30. wherein R2 and R3 are methyl.
28. The pharmaceutical composition according to 27. 31. The pharmaceutical composition according to claim 27, wherein R4 is hydrogen. (32) wherein R5 is 28. The pharmaceutical composition according to claim 27, wherein 33. The pharmaceutical composition according to claim 27, wherein the compound is an isolated d- or 1-enantiomer. 34. The pharmaceutical composition according to claim 33, wherein the compound is an isolated 1-enantiomer. (35) the compound, 28. The pharmaceutical composition according to claim 27, wherein (36) the compound, 28. The pharmaceutical composition according to claim 27, wherein 37. The pharmaceutical composition according to claim 36, wherein the compound is an isolated d- or 1-enantiomer. 38. The pharmaceutical composition according to claim 37, wherein the compound is an isolated 1-enantiomer. 39. The patient according to claim 27, wherein the patient is a post-menopausal woman.
A pharmaceutical composition according to claim 1. 40. The pharmaceutical composition according to claim 27, wherein the composition is in a form suitable for oral administration. 41. The pharmaceutical composition according to claim 27, wherein the compound is administered at a dosage of 0.1-5.0 mg / kg patient weight / day. 42. The composition of the present invention is administered at daily to weekly intervals.
28. The pharmaceutical composition according to claim 27. 43. The pharmaceutical composition according to claim 27, wherein the composition is in the form of a subcutaneous implant.